Fires and burns are among the most common causes of death from unintentional injury. In the United States, almost 1.2 million burn injuries are reported annually and despite significant advances in burn care, infection remains a major cause of morbidity and mortality in burn patients. A better understanding of a patient's response to the burn injury and the implications of secondarily acquired infections will have a profound impact on hospitalization, medical care, treatment and, survival of burn patients. Major thermal injury is associated with hypermetabolism and catabolism. For reasons that are not yet clearly understood, severe burns and trauma can lead to an uncontrolled and prolonged action of pro-inflammatory cytokines. The extent of the inflammatory response has been shown to inversely correlate with survival. Studies suggest that blunting the excessive inflammatory signal cascade may be an efficient strategy to improve patient outcomes after burn injury. Our proposal aims at addressing two questions: (i) what are the cellular and molecular signatures of prolonged inflammation;and (ii) what targets modulate the in vivo response. Specific Aim 1 will test the hypothesis that prolonged inflammation induces significant pathophysiological responses which can be characterized by monitoring dynamic changes in gene expression and metabolic fluxes. Specific Aim 2 will test the hypothesis that advanced bioinformatics methods can identify critical points of control of the inflammatory response. Specific Aim 3 will test the hypothesis that the hypermetabolic response can be modulated by interfering with the critical points of control identified in Aim 2. These studies represent a comprehensive approach integrating data at the gene expression, and metabolic flux levels obtained during the onset and maintenance of hypermetabolism. An investigative team has been assembled which brings together key expertise in burn animal models and hypermetabolism (Berthiaume), molecular bioengineering (Roth), metabolic engineering (Ierapetritou) and bioinformatics (Androulakis) PUBLIC HEALTH RELEVANCE: This proposal aims towards the understanding of the control mechanisms of the hypermetabolic response of burn-sepsis induced inflammation using data collected from an animal (rat) model. Our ultimate goal is to understand the systemic response in our efforts to, eventually, suggest improve therapeutic strategies for the recovery from severe burn injuries.